Rab5 in caveolin-1-driven cell migration

Rab small GTPases are membrane trafficking proteins that are conserved in all eukaryotes. Each Rab localises to a specific membrane and controls a specific step in the transport process. Rab5 localises to early endosomes and has a central role in regulating vesicle and early endosome dynamics. Recent evidence has also shown that Rab5 promotes Rac1 activation and cancer cell migration, but current knowledge about upstream regulators of Rab5 function remains limited. Having previously shown that the scaffolding protein caveolin-1 (CAV1) promotes Rac1 activation and the migration of cancer cells, Andrew Quest, Vicente Torres and colleagues (p. 2401) hypothesised that CAV1-stimulated Rab5 activation increases Rac1 activity and cell migration. The authors demonstrate that CAV1 promotes Rab5 activation in different metastatic cancer cells, including MDA-MB-231 human breast cancer, HT-29(US) human colon adenocarcinoma and B16-F10 mouse melanoma cells. The authors show that Rab5 activation by CAV1 is required for Rac1-GTP loading, and migration and invasion of metastatic cancer cells, as shown by increased expression and RNAi knockdown experiments. Moreover, CAV1 promotes the recruitment of the Rac1-guanine-nucleotide-exchange factor Tiam1 to Rab5-containing early endosomes. Accordingly, Tiam1 is required for both CAV1- and Rab5-dependent activation of Rac1 and cancer cell migration. Finally, the authors show that CAV1 recruits the Rab5 GTPase-activating protein p85α, thereby promoting Rab5 activation. Taken together, these findings suggest that there is a CAV1–Rab5–Rac1 signalling axis that is required for cancer cell migration and invasion.